MICA: Evaluation of anti diabetic drugs in the treatment of respiratory disease

肺的气道衬有一层薄薄的液体（气道表面液体，ASL），这对肺部防御感染很重要。为了优化其功能，ASL的体积和组成受到气道表面细胞（上皮）的严格调节。我们已经表明，ASL患者的葡萄糖（糖）浓度通常比血液中的低得多。我们的证据表明，这是一种保护机制，因为葡萄糖是包括感染性微生物在内的许多生物的生长基质。然而，当气道发炎时，血糖浓度升高（高血糖，与糖尿病或严重疾病相关），更可能的是，当炎症和高血糖同时存在时，ASL中的葡萄糖浓度升高。这使得呼吸道更容易受到感染，特别是病原体，如耐甲氧西林金黄色葡萄球菌（MRSA）和铜绿假单胞菌。我们已经建立了人气道上皮细胞模型，以了解ASL中葡萄糖浓度是如何调节的。我们已经证明，葡萄糖作用于基底外侧（血液）侧可以穿过上皮进入ASL。正常情况下，葡萄糖在上皮细胞间的移动受到限制。然而，当上皮发炎时，它变得更容易渗漏，使葡萄糖更容易通过。如果这与基底外侧葡萄糖浓度升高相结合（如糖尿病），则会有更多的葡萄糖通过。在这种情况下，我们发现ASL中细菌的生长增加。在一项令人兴奋的新进展中，我们用二甲双胍（一种已经在临床使用的药物）治疗上皮来阻止细菌的生长。二甲双胍的主要作用是防止葡萄糖进入ASL并支持细菌生长。这可能为治疗肺部疾病提供新的治疗途径，特别是考虑到细菌对抗生素治疗的耐药性增加。很难研究炎症和糖尿病如何增加ASL患者肺部的葡萄糖。因此，我们将使用我们的细胞模型和人类肺部疾病的动物模型来了解这是如何发生的。我们将研究二甲双胍是否可以降低ASL患者的葡萄糖浓度并抑制呼吸道感染。我们还将研究其他预测能减少葡萄糖进入ASL的药物是否会有类似的效果。此外，我们将测试正在开发的降低糖尿病患者血糖水平的新药是否具有附加的有益效果。这个项目将增加我们对ASL肺部疾病中葡萄糖是如何增加的以及血糖水平何时升高以及这两个事件是如何促进感染的理解。它还将告诉我们二甲双胍或其他药物是否可以减少葡萄糖在上皮中的运动或降低血糖，可以用于治疗这些疾病的患者。这可能会产生重要的经济和社会影响，特别是在富裕国家，那里的人口老龄化正在扩大，慢性病更为普遍，糖尿病的发病率也在增加。

The airways of the lung are lined with a thin layer of fluid (airway surface liquid, ASL) which is important for lung defence against infection. To optimise its function, the volume and composition of ASL are tightly regulated by the surface cells of the airway (epithelium). We have shown that the concentration of glucose (sugar) in ASL is normally much lower than that of blood. Our evidence indicates that this serves as a protective mechanism as glucose is a growth substrate for many organisms including infectious microbes. However, glucose concentration in ASL increases when the airways are inflamed, when blood glucose concentration is raised (hyperglycaemia, associated with diabetes or severe illness) and, more potently, when inflammation and hyperglycaemia are both present. This makes the airway more susceptible to infection particularly with pathogens such as methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. We have developed a cell model of human airway epithelium to understand how glucose concentration in ASL is regulated. We have shown that glucose applied to the basolateral (blood) side can get across the epithelium into the ASL. Normally the movement of glucose between the epithelial cells is restricted. However, when the epithelium becomes inflamed, it becomes leakier allowing glucose to pass across it more easily. If this is coupled with increased glucose concentration on the basolateral side (as in diabetes), even more glucose gets across. In this situation, we showed that the growth of bacteria in ASL was increased. In an exciting new development, we prevented the growth of bacteria by treating the epithelium with metformin (a drug already in clinical use). Metformin predominantly acted to prevent glucose getting into ASL and supporting bacterial growth. This could potentially provide a new therapeutic route for treatment of lung disease particularly in the light of increased resistance of bacteria to antibiotic therapy. It is difficult to investigate how inflammation and diabetes increase glucose in ASL in the lungs of human subjects. Therefore, we will use our cell model and animal models of human lung disease to gain an understanding of how this occurs. We will investigate whether metformin can reduce glucose concentrations in ASL and suppress respiratory infection. We will also investigate whether other drugs that are predicted to reduce glucose movement into ASL will have a similar effect. In addition, we will test whether new drugs that are being developed to reduce blood sugar levels in diabetes have an additive beneficial effect. This project will increase our understanding of how glucose is increased in ASL in lung disease and when blood sugar levels are raised and how these two events promote infection. It will also tell us whether metformin or other drugs that reduce glucose movement across the epithelium or reduce blood glucose could be used to treat patients with these conditions. This could have important economic and social impact particularly in wealthy countries where the ageing population is expanding, chronic illness is more prevalent and the incidence of diabetes is increasing.